AB0080 GDF-11 AND GDF-8 INVOLVEMENT IN MUSCLE IMPAIRMENT OF COLLAGEN-INDUCED ARTHRITIS MODEL
Authors: B. Bartikoski, M. Farinon, T. Hein da Rosa, R. T. Pedo, T. Karnopp, R. Cavalheiro do Espírito Santo, J. Miranda de Souza Silva, R. Xavier
Journal: Annals of the Rheumatic Diseases (2022)

Background Rheumatoid arthritis is an autoimmune, inflammatory disease which affects primarily synovial joints and can induce skeletal muscle wasting (1). It is known that growth differentiation factors 8, 11 plays an important role in muscle homeostasis (2-3). Objectives Evaluate muscle mRNA and protein expression of GDF-8, GDF-11 in early and established stages of collagen-induced arthritis. Methods DBA1/J mice, were randomized into 5 groups: baseline animals (BL=6); control animals evaluated at days 25 and 50 (CO25=8, CO50=8) and collagen-induced arthritis mice evaluated at day 25 and 50 (CIA 25=8; CIA 50=8). Clinical score, paw edema, and body weight were evaluated. Clinical score, hind paw edema, and body weight were assessed. Grip strength, nociception, fatigue time, and walking speed were assessed on days 0, 18, 25, 50 of experimentation. Animals were euthanized on days zero (BL group), 25 (CIA 25 and CO 25) and 50 (CIA 50 and CO 50) after disease induction. TA muscle was used to myofiber cross-sectional and GA muscle was used to evaluate gene expression of GDF-8, GDF-11 levels via qRT-PCR. Protein expression of GDF-8, GDF-11 levels in GA muscle was performed by ELISA. Results RA in the early CIA 25 and established CIA 50 groups was confirmed by high values of clinical score, nociception, paw edema and histological score when compared to the respective controls (p&lt;0.0001; p=0.001; p=0.001). There was a decrease in grip strength in the CIA 25 group and a worsening in this decrease at CIA 50 (p=0.0021, p=0.007). Fatigue time was shorter in CIA 25 compared to CO 25 (p= 0.002) and maintained in CIA 50 (p= 0.006). Walking speed showed a decrease in both time points (p=0.001; p=0.000). After normalization by body weight, only the GA muscle had weight loss in CIA 50 when compared to CO 50 (-34.5%). Similarly, the CSA TA muscle myofiber showed a reduction of 14.04% only at CIA 50 group compared to the CO 50 (p=0.026). The GA muscle GDF-11 mRNA levels were higher in the CIA 25 group compared to the CO 25 and BL groups (p=0.004; p=0.0087, respectively); in CIA 50, there was a trend towards increased muscle GDF-11 mRNA levels (p=0.07). The protein expression of GDF-11 in serum samples did not show differences between the analyzed groups; however, in GA muscle, GDF-11 protein expression showed differences at the CIA 25 (p=0.0023) and the CIA 50 group (p=0.017) compared with the respective controls and a significant difference in muscle protein expression between the CIA 25 groups and CIA 50 (p=0.0138). There was a decreased of mRNA content GDF-8 on muscle, in CIA 50 and a decreased between the CIA 25 and CIA 50 in GA muscle (p= 0.0377; p= 0.0019); GA muscle had an increase of GDF-8 protein levels comparing the CIA 25 and CIA 50 group (p=0.001), while protein levels in serum of GDF-8 were decreased in CIA 50 compared with CO 50 (p= 0.037). Low muscle strength was associated with higher protein levels of GDF-11 in GA muscle (r= -0.64, p=0.01) and decreased walking speed (r=-0.534, p=0.04). Higher serum levels of GDF-8 were associated with higher muscle strength (r= 0.74, p=0.02) and increased walking speed (r= 0.64, p=0.01). Conclusion At early arthritis, GDF-11 mRNA and protein expressions were increased and are related to the physical impairment, while GDF-8 expression is reduced at established disease and increased in serum over time in CIA model, possibly as GDF-8 had a more systemic role in inflammatory arthritis. Thus, the GDFs may have a role in muscle outcomes in the CIA model and can be involved in muscle atrophy and loss of physical function in RA. References [1]Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA - J Am Med Assoc. 2018;320(13):1360–72. [2]Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, et al (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344: 649–52. [3]Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S &amp; Glass DJ (2009) Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Physiol 296: C1258–C1270. Acknowledgements We thank the Animal Experimentation Unit from the Hospital de Clínicas de Porto Alegre (HCPA) for their help during animal experimentation. Disclosure of Interests None declared